Diabetes mellitus has become pandemic and according to a forecast by the World Health Organization, there will be a sharp increase in the number of diabetic patients by the year 2030. This is an ominous forecast, because managing the long-term complications of diabetes, which include nephropathy, neuropathy, retinopathy, and cardiovascular complications, will have a serious impact on public health budgets. The hallmark of diabetes is chronically elevated blood glucose levels. It is also known that abnormally elevated glucose levels have an adverse impact on glutathione levels in key diabetic tissues. Furthermore, increased oxidative stress and increased production of reactive oxygen species are implicated under hyperglycemic conditions.
In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory.
The use of insulin requires multiple daily doses, usually by self-injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in urine or blood. Treatment of non-insulin dependent diabetes mellitus (type 2) diabetes (NIDDM) usually involves a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidenediones, and, in more severe cases, insulin. However, the clinically available hypoglycemic agents can either have side effects limiting their use, or may not be effective with a particular patient. In the case of insulin dependent diabetes mellitus (Type 1), insulin administration usually constitutes the primary course of therapy.
The biguanide metformin is a known compound approved by the U.S. Food & Drug Administration for the therapeutic treatment of diabetes. The compound and its preparation and use are disclosed, for example, in U.S. Pat. No. 3,174,901. Metformin is orally effective in the treatment of type 2 diabetes. Metformin (N,N-dimethylimidodicarbonimidic diamide) is a biguanide, anti-hyperglycemic agent currently marketed in the United States in the form of its hydrochloride salt, 1,1-dimethylbiguanide hydrochloride (Formula I):
Metformin hydrochloride can be purchased commercially and can also be prepared, for example, as disclosed in J. Chem. Soc., (1922), 121, 1790.
U.S. Pat. No. 7,973,073 B2 (Mylari) describes a method for treating diabetes or diabetic complications using metformin R-(+) lipoate.
According to United Kingdom Perspective Diabetes Study (UKPDS) (Clarke et al. Diabetologa, (2005), 48, 868-877), metformin therapy was cost-saving and increased quality-adjusted life expectancy. In the UKPDS, overweight and obese patients randomized to initial therapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with Type 2 diabetes.
Alpha-lipoic acid, commonly known as lipoic acid, has a variety of names, including thioctic acid, 1,2-dithiolane-3-pentanoic acid, 1,2-ditholane-3-valeric acid, 6,8-thioctic acid5-[3Cl,2-dithiolanyl)]-pentanoic acid, delta-[3-(1,2dithiacyclopentyl)]pentanoic acid and pyruvate oxidation factor. Alpha lipoic acid has an asymmetric center and is usually employed in the form of a racemic mixture of its R- and S-enantiomers, particularly in nutritional supplements. All published clinical trials have thus far been conducted with racemic alpha-lipoic acid.
Alpha-lipoic acid (herein referred to as lipoic acid) is an antioxidant and is a scavenger of reactive oxygen species (ROS). It chelates metals and recycles endogenous antioxidants. Lipoic acid can scavenge singlet oxygen, H2O2, hydroxyl radical, NO, and ONOO−. The reduced form of lipoic acid, dihydrolipoic acid, can further scavenge O2−, and peroxy radicals. Lipoic acid can also chelate several divalent cations, e.g., Mn2+, Cu2+, Zn2+, Cd2+, and Pb2+. Therefore, lipoic acid can inhibit ascorbate-induced production of H2O2 by Cu2+. Lipoic acid can recycle endogenous antioxidants, such as glutathione (GSH), and vitamin C. GSH protects tissues from oxidative stress. Lipoic acid can also circulate plasma levels of lactate and pyruvate in diabetic patients. Estrada et al., (Diabetes. 1996, 45, 1798-1804) report that lipoic acid induces GLUTs (glucose transporters) and glucose uptake and this suggests that lipoic acid may also stimulate the insulin signaling pathway. Lipoic acid administration has been shown to be active in oxidative stress models including in ischemia-reperfusion injury model. Furthermore, lipoic acid can function as a redox regulator of thioredoxin and NF-kappa B transcription factor. Many of the aspects of lipoic acid described herein are included in the review by Smith et al., Current Medicinal Chemistry (2004), 11, 1135-1146.
While lipoic acid is practically insoluble in water (Merck Index, 11th ed. at 9259), the salts of the present invention are markedly more water soluble to provide concomitant delivery of both metformin and lipoic acid, thus providing a dual action in targeting both blood glucose control and long-term diabetes complications, such as nephropathy, neuropathy, retinopathy, cataracts and cardiovascular complications. Furthermore, the new salts would offer a patient friendly dosage form of two active therapies in a fixed dosage combination with increased reliability for daily patient compliance.
Prediabetes is a syndrome. Many patients with type 2 diabetes and with a prediabetic condition known as metabolic syndrome suffer from a variety of lipid disorders including elevated triglycerides. The body uses triglycerides to store fat, but high (>200 mg/dl) and very high (>500 mg/dl) triglycerides are associated with atherosclerosis which increases the patients' risk of heart attack and stroke.
Incipient diabetes with impaired glucose tolerance is another prediabetic condition. Overall, type 2 diabetes and incipient diabetes with impaired glucose tolerance are intimately intertwined with obesity, hyperlipidemia, including hypertriglyceridemia, and cardiovascular complications including arrhythmia, cardiomyopathy, myocardial infarction, stroke and heart failure. Clinically, pre-diabetes means that blood sugar level is higher than normal, but it's not yet increased enough to be classified as type 2 diabetes. Still, without intervention, prediabetes is likely to become type 2 diabetes over time.
Diabetic complications include cataracts, nephropathy, neuropathy, retinopathy, and cardiovascular complications, including myocardial ischemia, cardiomyopathy, and heart failure.
Also, diabetic patients have impaired circulation that manifests itself in peripheral vascular disease (PVD) and the slow healing of wounds in the foot and lower leg and puts the patient at risk for amputation.
Each of the citations herein, whether patents or publications, is incorporated by reference.